Graves Gilbert Clinic

Gene therapy for Neurofibromatosis type 1 (NF1), defined as a collection of approaches that restore the quantity and function of neurofibromin, holds promise for treating various NF-associated clinical manifestations by addressing the root cause of the condition. The Gilbert Family Foundation’s Gene Therapy Initiative (GTI) launched one of the first focused research efforts to support a broad array of gene replacement, gene editing, and other strategies aimed at upregulating neurofibromin levels to mitigate symptoms and advance therapies for NF1. Efforts to discover and evaluate novel gene therapies to treat NF1 are hindered by foundational gaps in the field, the absence of quantitative assays, and a lack of robust preclinical models with reliable functional readouts. This perspective begins by shedding light on those key barriers that continue to hinder progress in NF1 gene therapy, outlines some of the strategies being explored to overcome them and offers pointers to additional strategies that merit further exploration. We then highlight several promising gene therapy strategies now in development. Successfully addressing the challenges described earlier is critical to realizing the full potential of these emerging and novel therapeutic approaches, setting the stage for effective and durable NF1 gene therapy interventions.

Down syndrome (DS) or trisomy 21 is one of the most common causes of intellectual disability, and recent national prevalence estimates indicate that there are 11.8–14.47 per 10,000 live births in the United States with DS. Furthermore, the World Health Organization estimates for DS range between 10 and 11 per 10,000 live births worldwide. This chapter discusses DS as it affects intellectual and cognitive development and magnifies issues of cognitive brain aging. DS has been linked to dementia. The neurological, biomarker, behavioral, and physical manifestations, and their potentially moderating effects on cognitive functioning of individuals with DS, are described. Proposed mechanisms of action between DS and Alzheimer’s disease and suggestions for intervention and future treatments are discussed.

Purpose. The increased use of magnetic resonance imaging (MRI) has resulted in reports of incidental abnormal bone marrow (BM) signal. Our goal was to determine the evaluation of an incidental abnormal BM signal on MRI and the prevalence of a subsequent oncologic diagnosis. Methods. We conducted a retrospective cohort study of patients over age 18 undergoing MRI between May 2005 and October 2010 at Tufts Medical Center (TMC) with follow-up through November 2013. The electronic medical record was queried to determine imaging site, reason for scan, evaluation following radiology report, and final diagnosis. Results. 49,678 MRIs were done with 110 patients meeting inclusion criteria. Twenty two percent underwent some evaluation, most commonly a complete blood count, serum protein electrophoresis, or bone scan. With median follow-up of 41 months, 6% of patients were diagnosed with malignancies including multiple myeloma, non-Hodgkins lymphoma, metastatic non-small cell lung cancer, and metastatic adenocarcinoma. One patient who had not undergone evaluation developed breast cancer 24 months after the MRI. Conclusions. Incidentally noted abnormal or heterogeneous bone marrow signal on MRI was not inconsequential and should prompt further evaluation.

Purpose: Data about gender based differences in response rates to treatment of CHC is limited. The aim of our study was to evaluate the gender based differences in predictors of early viral response rates and hematological abnormalities in patients with CHC infection. Methods: Over a period of 4 years, we reviewed the records of all patients with CHC who were started on treatment with weight adjusted pegylated interferon and ribavarin. Demographic, serological and laboratory data were collected. Insulin resistance was defined as a triglyceride (TG)/high density lipoprotein (HDL) ratio ≥ 3. Early virologic response (EVR) was defined as log10 HCV RNA level reduction of at least 2.0 logs or HCV RNA negativity by week 12. Patients were defined as having hematological abnormalities if they had the presence of thrombocytopenia, neutropenia, anemia or a combination of the above. Results: Of the 152 patients, 73 (48%) of the patients were males. On univariate analysis in males, EVR was significantly associated with an AST/ALT ratio ≥ 1 (P= 0.03), TG/HDL ≥ 3 (P= 0.005), Genotype 1 infection (P= 0.02) and higher age (P= 0.04). On multivariate analysis, insulin resistance was the only factor significantly associated with an EVR in males (OR 0.13 95% CI 0.03 –0.61 P value 0.009). Low baseline platelet count was the only independent factor significantly associated with hematological abnormalities in males (P= 0.01). On univariate analysis in females, EVR was associated with Genotype 1 (P= 0.02) and Nonwhite Race (P= 0.0009). Nonwhite race (P= 0.02) was the only factor significantly associated with EVR in multivariate analysis. None of the factors were significantly associated with hematological abnormalities in females. Conclusion: Insulin resistance is a significant predictor of EVR in CHC infection in males while in females nonwhite race is the most significant predictor of EVR.

Pediatrics has consistently attracted a large number of women. Although the majority of practicing pediatricians are male, female pediatricians will soon constitute the majority. The challenge to balance personal and professional life is of particular concern to women, and part-time positions may provide a potential solution. To examine how many pediatricians currently work part-time, to examine trends in part-time employment from 1993 to present, to determine pediatric residents' interest in part-time employment, and to identify perceived barriers to part-time work. Two data sources were used for these analyses. The first was an American Academy of Pediatrics Periodic Survey from 1993 and 2000 asking a combined national sample of 3218 American Academy of Pediatrics members about their employment status. Multiple mailings were conducted for each survey producing an overall response rate of 62%. The second data source was a survey asking a national random sample of 500 pediatric residents completing training in 2000 about their job search experiences and attitudes toward part-time employment. Four mailings of this survey were completed, and responses were obtained from 71% of residents. The percentage of pediatricians working part-time increased from 11% in 1993 to 15% in 2000. This increase did not exceed what would be expected based on the rise in the percentage of pediatricians who are female from 36% in 1993 to 45% in 2000. On average, pediatricians working part-time provided 36% fewer direct patient care hours than full-time pediatricians (42 hours vs 27 hours). No statistically significant difference in direct patient care hours was apparent between male and female pediatricians working full-time. Female residents were more likely than male residents to consider part-time or reduced-hours positions (42% vs 14%) and to accept part-time or reduced-hours positions (14% vs 3%). Also, considerably more female residents (58%) than male residents (15%) indicated that they would be interested in arranging a part-time position within the next 5 years. The most commonly perceived barriers to working part-time by both male and female residents included loss of income (70%), reduction in job benefits such as health insurance (47%), and loan repayment (46%). When those who reported some interest in part-time employment were asked how they would spend their extra time, most reported that they would address family needs related to children (females: 92%; males: 63%). Finally, residents interested in working part-time were more likely to be without a position when surveyed than residents not interested in part-time work (15% vs 2%). The relative percentages of female pediatricians and pediatricians working part-time will likely continue to grow. As a result, the total direct patient care hours available for children may be reduced. Pediatric practices will benefit by better accommodating the needs of pediatricians to balance work and family goals, and future workforce projections and training decisions must begin taking part-time employment rates into account.

Four experienced coronary angiographers (two radiologists and two cardiologists) independently assessed the location and degree of coronary artery stenosis, and the location and degree of left ventricular wall motion abnormalities in 20 coronary angiograms. Marked interobserver variability was noted in quantifying percent coronary artery stenosis and degree of left ventricular wall motion abnormalities. For example, in only 13/20 (65%) of the coronary angiograms did all observers agree about the significance of a stenosis (defined as greater than 50% in diameter luminal narrowing) in the proximal or mid left anterior descending coronary artery. In 3/20 (15%) angiograms there was disagreement by at least one observer about the significance of lesions noted in the main left coronary artery. The ventricle was divided into five segments and the degree of wall motion abnormality graded into six categories of increasing severity from normal to dyskinesis. There was a 42% mean disagreement among all four observers where a disagreement between observers was defined as any difference in grading wall motion abnormalities. Interobserver variability reveals a significant limitation of coronary angiography.

The intricate faulting in the Mississippian and Pennsylvanian formations of western Kentucky has been usually correlated with the Appalachian orogeny. Post-Paleozoic sediments are all unconsolidated and evidence of post-Appalachian faulting is consequently obscure; references to the possibility of later faulting have heretofore been largely unsupported by specific evidence. Detailed examination of the area establishes the occurrence of later faulting. Just as the epeirogenic disturbances in this region at the end of the Paleozoic era were associated with important faulting, the similar but less intense epeirogenic movements during the Cretaceous and Eocene periods led to renewed faulting--probably, however, on a smaller scale.